4-oxo-1,8-naphthyridine-3-carboxylates and derivatives thereof

ABSTRACT

4-Oxo-1-substituted-1,8-naphthyridine-3-carboxylic acid derivatives, having antibacterial properties, prepared by 1alkylating corresponding 4-hydroxy-1,8-naphthyridine-3-carboxylic acid derivatives.

United States Patent Lesher et al.

[ 1 June 27, 1972 Assignee:

4-OXO-1,8-NAPHTHYRID1NE-3- CARBOXYLATES AND DERIVATIVE THEREOF George Y.Lesher, Schodack; Monte D. Gruett, East Greenbush, both of N.Y.

Sterling Drug Inc., New York, NY. Filed: May 11, 1970 Appl. No.1 36,454

Inventors:

Related US. Application Data Division of Ser. No. 399,333, Sept. 25,1964, abandoned, Continuation-impart of Ser. No. 244,886,

Dec. 17, 1962, abandoned, Continuation-impart 0fSer.No.79,951,.Ian.3,l96l,Pat.N0.3,l49,104.

.... ..260/295.5 B, 260/240 D, 260/999 ..C07d 31/36 ..260/295.5 B, 295.5N

US. Cl.

Int. Cl.

Field of Search Primary Examiner-Alan L. Rotman Att0meyE1mer J. Lawson,B. Woodrow Wyatt, Thomas L.

Johnson, Robert K. Bair, William G. Webb'and Roger T..

Wolfe ABSTRACT 4-Oxo-1-substituted-l ,8-naphthyridine-S-carboxylic acidderivatives, having antibacterial properties, prepared by l-alkylatingcorresponding 4-hydroxy-l,8-naphthyridine-3-carboxylic acid derivatives.

10 Claims, No Drawings 4-OX0- l ,8-NAPHTI-IYRIDINE-3-CARBOXYLATES ANDDERIVATIVES THEREOF This application is a division of our applicationSet. No. 399,333, filed Sept. 25, 1964, now abandoned, which in turn isa continuation-in-part of our application Ser. No. 244,886, filed Dec.17, 1962, now abandoned, which in turn is a continuation-in-part of ourapplication Ser. No. 79,951, filed Jan. 3, 1961, now US. Pat.No.3,149,104, issued Sept. 15, 1964.

This invention relates to l,8-naphthyridines and particularly to1,3-disubstituted-4-oxo compounds thereof, and to their preparation.

The invention sought to be patented, in its1,3-disubstituted-4-oxo-1,8-naphthyridine aspect, is described asresiding in the concept of a chemical compound having a molecularstructure in which an organic radical having up to and including 18carbon atoms and having a molecular weight not over 700 is attachedthrough a saturated carbon atom thereof to the l-nitroge'n atom of3-X-4-oxo-l,8-naphthyridines and 5,6,7,8-tetrahydro derivatives thereofwhere X stands for carboxy or a group convertible thereto by hydrolysis.

The physical embodiments of our invention have been tested by standardbacteriological and pharmacological evaluation procedures and found tohave antibacterial, stimulant and sedative properties. They are alsouseful as inter mediates in organic syntheses.

Illustrative and preferred embodiments of our 1,3-disubstituted-4-oxol,8-naphthyridines are those having the fonnula 1 where X is carboxy andsalts thereof,carbalkoxy having from two to 19 carbon atoms inclusive,carbo-[(lower-tertiaryamino polycarbon-lowcr-alkoxy 1, yano, carbamyl,aminocarhamyl or other groups convertible to carboxy by hydrolysis, Y isdivalent aliphatic hydrocarbon attached to the ring-nitrogen atomthrough a saturated carbon atom and having from one to 10 carbon atomsinclusive, Z is a member of the group consisting of hydrogen, hydroxy,halo, carboxy, lower-carbalkoxy, cyano, carbamyl, lower-hydrocarbonoxy,lower-secondary-amino, lower-tertiary-amino, lower-cycloalkyl and AR,and Q stands for hydrogen or from 1 to 4 lowmolecular weightsubstituents at positions 2,5,6 and 7 of the naphthyridine nucleus, saidsubstituents selected from the group consisting of lower-alkyl,lower-alkoxy, lower-alkylmercapto, lower-alkyl-sulfinyl,lower-alkylsulfonyl, halo, hydroxy, hydroxy-(lower-alkyl),lower-alkoxy-(lower-alkyl), (lower-carboxylic-acyloxy)-(lower-alkyl),lower-alkyl-arnino, di-(lower-alkyl)amino, nitro, amino, hydrazino,lower-carboxylic-acylamino, trihalomethyl, lower-alkanoyl,lower-alkanoyloxy, (lower-tertiary-amino )-(polycarbon-lower-alkyl)(lower-secondary-amino)-(polycarbon-lower-alkyl),(lowertertiary-amino)-(polycarbon-lower-alkylamino),(lowersecondary-amino polycarbo n-lower-alkylamino(lowertertiary-amino)-(polycarbon-lower alkoxy),(lower-secondary-amino)-(polycarbon-lower-alkoxy), AR, AR-O, AR-S, AR-NH, AR-(lower-alkyl), lower-cycloalkyl, lower-cycloalkyloxy,

lower-cycloalkylmercapto, lowcr-cycloalkylamino,lowercycloalkyl-(lower-alkyl), AR-(lower-alkenyl),AR-(halolower-alkenyl), AR-(lower-alkenyl), AR-C( AR- CH(CN),'AR-CH(OH), AR-O-Cl-l AR-(lower-alkoxy), cyano, triazo;amino-(lower-alkyl), (lower-carboxylicacylamino)-(lower-alkyl),carbamyl, carboxy and lower-carbalkoxy, where AR is l-2 ringed aryl.Unless otherwise indicated hereinabove or hereinbelow, the word lower"when used with an alkyl moiety means alkyl, either straightorbranch-chained, having from one to six carbon atoms inclusive, e.g.,lower-alkoxy stands for methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,2-butoxy, i-butoxy, n-pentoxy, 3-pentoxyan d n-hexoiry. Particularlypreferred embodiments of our When Z of Formula I is hydrogen Z-Y meansaliphatic v hydrocarbon radicals having from one to 10 carbon atomsinelusive and having a saturated carbon atom linked to the lnitrogenatom of the 1,8-naphthyridine ring, and comprehends alkyl, alkenyl andalkynyl radicals, as illustrated by methyl, ethyl, n-propyl, isopropyl,2-butyl, isoarnyl, n-hexyl, noctyl, n-decyl, and the like, when alkyl;Z-propenyl (allyl), 2- methyl-Z-propenyl, 3-butenyl, 2-hexenyl, and thelike, when alkenyl; and 2-propynyl (propargyl), 3-butynyl, 2-octynyl,and the like when alkynyl. When Z is other than hydrogen, as named aboveand illustratedbelow, the term Z-(aliphatichydrocarbon)," i.e., Z-Y- asused in Formula I, means the above illustrated aliphatic-hydrocarbonradicals substituted by radicals as named above for Z and as furtherillustrated below or, in other words, Y or aliphatic-hydrocarbon" is adivalent aliphatic hydrocarbon radical having from one to 10 carbonatoms and is linked to the ring-nitrogen atom of the naphthyridinenucleus through a saturated carbon atom.

The term lower-carbalkoxy, as used herein, e.g., for Z in Formula I,means carbalkoxy radicals where the alkoxy portion can be straightorbranch-chained and has from one to six carbon atoms, as illustrated bycarbomethoxy, carbethoxy, carbo-n-propoxy, carbisopropoxy,carbo-n-butoxy, carbo-nhexoxy, and the like. Where 2 islower-carbalkoxy, Z-Y is exemplified by carbomethoxymethyl,4-carbethoxybutyl and 3- carbo-n-butoxy-Z-propenyl.

The term lower-hydrocarbonoxy, as used herein, means hydrocarbonoxyradicals having from one to eight carbon atoms where hydrocarbon is, forinstance, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,unsubstituted-phenyl, alkylated-phenyl, benzyl or phenethyl, as furtherillustrated by methyl, ethyl, n-propyl, isopropyl, 2-butyl, isoamyl,n-hexyl, and the like, when alkyl; etheny1(vinyl), 2-propenyl,3-but'enyl, 2-hexenyl, and the like, when alkenyl;2-propynyl(propargyl), 3-hexynyl, and the like, when alkynyl;cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and thelike, when cycloalkyl; cyclopropylmethyl, cyclopropylethyl,cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, and the like, whencycloalkylalkyl; 2-methylpheny1, 4- methylphenyl, 2,4-dirnethylphenyl,3-ethylphenyl, and the like, when alkylated-phenyl. When 2 islower-hydrocarbonoxy, Z-Y is, e.g., 2-ethoxyethyl,3-(2-propenoxy)-propyl and 4- phenoxy-2-butenyl.

The term lowercycloalkyl, as used herein, means cycloalkyl radicalshaving from three to eight ring-carbon atoms and having up to a total ofabout eight carbon atoms, as illustrated by cyclopropyl, cyclopentyl,cyclohexyl, 2-methylcyclohexyl, 4-ethylcyclohexyl, cyclooctyl, and thelike. When Z is lower-cycloalkyl, Z-Y is, e.g., 4-cyclopropylbutyl and2- cyclohexylpropyl.

The term l-2 ringed aryl, as used herein, e.g., as AR for Z or Q inFormula I, means radicals having one or two aromatic rings which can bebenzenoid or fiveor six-membered hetero-aromatic, as illustrated byphenyl, naphthyl, biphenylyl, pyridyl, pyrimidyl, furyl, thiazolyl,quinolyl, oxazolyl, triazinyl, thienyl, and the like. Preferredembodiments of 1-2 ringed aryl, because of their commercialpracticability due to availability of intermediates, are those where ARis phenyl,

the benzene ring of which can bear low-molecular weight substituents,among which are, for purposes of illustration but without limiting thegenerality of the foregoing, lower-alkyl, lower-alkoxy,lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl,. halo,lower-alkylamino, di-(lower-alky'l)amino, nitro, amino,lower-carboxylic-acylamino, trihalomethyl, phenoxy, benzyloxy, benzoyl,lower-alkanoyl, (lower-tertiary-amino)-(polycarbon-lower-alkyl),secondary-amino)-(polycarbon-lower-alkyl), (lower-tertiary- (loweramino)-(polycarbon-lower-alkylamino), amino)-(polycarbon-lower-alkylamino),amino)-( polycarbon-lower-alkoxy), amino)-(polycarbon-lower-alkoxy),

(lower-secondary- (lower-tertiary- (lower-secondaryhydroxy, cyano,

aminomethyl, carbamyl, carboxy, lower-carbalkoxy, unsub- CH(CH )CHCH,Cl-l

' and the like.

stituted-phenylrnercapto, benzyl, -4-niethoxyphenoxy, and the like. Whenthe benzene ring is substituted, there are preferably from one to threesubstituents which can be in any of the available positions of thebenzene ring, and where more than one substituent is present, they canbe the same or different and they can be in any of the various positioncombinations relative to each other. The lower-alkyl, lower-alkoxy,lower-alkylmercapto, lower-alkyl-sulfinyl, lower-alkylsulfonyl,lower-alkylamino, lower-carboxylic-acylamino, lower-alkanoyl and thelike substituents have preferably from one to six carbon atoms which canbe arranged as straight or branched chains, and are illustrated bymethyl, ethyl, n-hexyl, methoxy, isobutoxy, ethylmercapto,n-amylmercapto, methylsulfinyl, n-propylsulfinyl, isopropylsulfonyl,n-butylsulfonyl, ethylamino, n-butylamino, acetylamino, propionylamino,acetyl, propionyl, and the like. When AR is other than phenyl, e.g.,naphthyl, biphenylyl, pyridyl, pyrimidyl, furyl, thiazolyl, quinolyl,oxazolyl, triazinyl, thienyl, 'etc., the rings thereof can bearsubstituents such as those listedabove as substituents for the benzenering. When Z is AR, AR-Y- is, e.g., 4- chlorobenzyl, 2-(2-pyridyl)ethyl,I 6-(3,4-dirnethoxyphen yl)hexyl and 2-(3,4-dibromophenyl)ethyl.

The term lower-secon dary-amino, as used herein, means secondary-aminoradicals having preferably from one to about eight carbon atoms, asillustrated by: monocycloalkylamino radicals where the cycloalkyl grouphas preferably from three to eight ring-carbon atoms such radicalsincluding cyclopropylamino, cyclobutylamino, cyclopentylamino,cyclohexylamino and cyclooctylamino; mono-(lower-hydroxyalkyl)aminoradicals where the lower-hydroxyalkyl group has preferably two to sixcarbon atoms such radicals including 2- hydroxyethylarnino,3-hydroxypropylamino, 4-hydroxybutylamino, 2hydroxypropylamino,6-hydroxyhexyl-amino, etc.; mono-(lower-alkyl)amino radicals where thelower-alkyl group has preferably from one to six carbon atoms suchradicals including methylamino, ethylamino, n-propylamino,isopropylamino, n-butylamino, Z-butylamino, isobutylamino, n-amylamino,n-hexylamino, etc.; mono-[(mono-carbocyclicaryl)methyl]amino radicals,such radicals including benzylamino, 2-chlorobenzylamino, 3,4-dichlorobenzylamino, 3-nitrobenzylamino, 3,4-diethoxybenzylamino,4-isopropylbenzylamino, 2,4,6-

.trichlorobenzylamino, etc.; and the like.

The term lower-tertiary-amino, as used herein means tertiary-aminoradicals having two nitrogen substitue nts such as those illustratedabove for the lower-secondary-amino radicals, with preferredtertiary-amino radicals being di-(lower-alkyl)-amino radicals where thelower-alkyl radicals are alike or different and each alkyl radical haspreferably from one to six carbon atoms, such dialkylamino radicalsdimethylamino, diethylamino, ethyl-methylamino, diisoproylamino,ethyl-n-propylamino, di-n-butylamino, di-nhexylamino, and the like. Thisterm lower-tertiary-amino also comprehends saturated N-heteromonocyclicradicals having five to six ring atoms, illustrated by l-piperidyl;(loweralkylated)-l-piperidyl such as 2-methyl-l -piperidyl,3-ethyl-lpiperidyl, 4-methyl-l-piperidyl, 2,6-dimethyll-piperidyl;lpyrrolidyl; (lower-alkylated)-l-pyrrolidyl such as2-methyl-lpyrrolidyl, 3-ethyl-1-pyrrolidyl, 2,5-dimethyl-l-pyrrolidyl;4- morpholinyl; l-piperazyl; alkylated-l-piperazyl such as 4-methyl-l-piperazyl, 4-ethyl-l-piperazyl, 2,4,6-trimethyl-lpiperazyl; andthe like.

When Zstands for lower-secondary-amino or lower-tertiary amino, Y ispreferably polycarbon-lower-alkyl and Z-Y is illustrated by2-(2-hydroxyethylamino)ethylamino, 4- dimethylaminobutyl and 3(l-piperidyl)propyl.

The term polycarbon-lower-alkyl," as used herein, means lower-alkyleneradicals preferably having from two to six carbon atoms and having itsconnecting linkages on different carbon atoms, e.g., CH CH CH CH CH CHCl-l CH CH including.

The term halo, as used herein as substituents for the naphthyridinering, i.e., as Q, or as substituents for the loweraromatic ring, meanschloro, bromo, iodo, or fluoro.

The tenn lower-carboxylic-acyl," as used herein, e.g., as a part ofseveral meanings for Q, means lower-alkanoyl, lowerhaloalkanoyl,lower-carboxyalkanoyl, (lower-tertiary-amino)- (lower-alkanoyl), andmonocarbocyclic-aroyl, illustrated by forrnyl, acetyl, chloroacetyl,dichloroacetyl, propionyl, B-can.

practically completely dissociated in aqueous solution. The

organic moiety of the ester has up to and including 18 carbon atoms, hasa molecular weight not over 700 and is attached to the anionic portionof the ester through a saturated carbon atom thereof. Illustrative andpreferred organic esters are estersof a strong inorganic acid or anorganic sulfonic acid,

said ester having the formula Z-(aliphatic-hydrocarbon)-An, or Z-Y-An,where An is an anion of a strong inorganic acid or an organic sulfonicacid, e.g., chloride, bromide, iodide, sulfate, benzenesulfonate,para-toluenesulfonate, and the like, and Z and Y have the meaningsgivenabove for Formula I. The chloride, bromide or iodide is preferredbecause of the more ready availability of the requisiteZ-(aliphatic-hydrocarbon) halides; and the reaction is carried outpreferably in the presence of an acid-acceptor. The acid-acceptor is abasic substance which preferably forms freely water-soluble byproductseasily separable from the product of the reaction, including forexample, sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium alkoxides, potassium alkoxides, sodiumamide, and the like. The purpose of the acid-acceptor is to take up thehydrogen halide (or l-lAn) which is split out during the course of thereaction. The

reaction can be carried out either in the presence or absence of asuitable solvent, but preferably in a solvent such as a lower-alkanol,acetone, dioxane, dimethyl sulfoxide, or a mixture of such solvents,e.g., a mixture of water and a lower-alkanol. The reaction is generallycarried out at a temperature between about room temperature (about 25C.) and C., preferably at reflux, in a lower-alkanol' solvent, a mixtureof water and a lower-alkanol, or dimethylformamide.

To illustrate the preparation of the preferred1,3-di-substituted-4-oxo-1,8:naphthyridines of our invention havingformula l, our process comprises reacting the corresponding 3-X-4-hydroxy-1 ,8-naphthyridine having the Formula II dimethylformamide,

yield the corresponding l-(Z-Y)-4-oxo-l,8-naphthyridine-3- carboxylicacid; the same 3-carboxylic acid is also obtained using these reactionconditions and a lower-alkyl 4-hydroxyl,8-naphthyridine-3-carboxylate asthe intermediate, the ester hydrolyzing under the. reaction conditionsto form the acid. If the final product is desired in ester form,e.g.,the ethyl ester, the intennediate ethyl4-hydroxy-1,8-naphthyridine-3-carboxylate is reacted as above usingrefluxing ethanol as the solvent and sodium ethoxide as theacid-acceptor. The alkylation of the4-hydroxy-l,8-naphthyridine-3-carboxylic acid can be carried out in theabsence of an acid-acceptor by using its disalt, e.g., by heating amixture of the anhydrous dipotassium or disodium salt with diethylsulfate followed by acidification to obtain the l-ethyl-4-oxo-l,8-naphthyridine-3-carboxylic acid.

Some of the intermediate 4-hydroxy-l,8-naphthyridine-3- carboxylic acidsand derivatives are known, e.g., 4-hydroxy-7-methyll,8-naphthyridine-3-carboxylic acid and ethyl ester, 7-ethoxy-4-hydroxy-1,8-naphthyridine-3-carboxylic acid and ethyl ester,and 4-hydroxyl ,8-naphthy-ridine-3-carboxylic acid. Other suchintermediates, where novel, are prepared by generally known methodswhich are illustrated hereinbelow.

For example, the intermediate lower-alkyl 4-hydroxy-l,8-

naphthyridine-S-carboxylate is obtained in two steps by first reacting a2-aminopyridine with one molar equivalent of a di- In its broaderaspect, our invention encompasses not only the aforementionedl-substituted-3-X-4-oxo-1,8- naphthyridines where X stands for carboxyand salt, ester, amide and hydrazine derivatives thereof but also forcorresponding compounds where X-stands for other groups convertible tocarboxy by hydrolysis, e.g., where X stands for C( NH)O-(lower-alkyl),C(NH)NH,,C( NH)Nl-l(lower-alkyl),C( S)OH, C( S)SH and C( O)-halide.

Other compounds encompassed by our invention are biscompounds preparedby our process using bis-esters having the formula An-Y-An' where Y hasthe'meaning given above for Formula I and where, in each instance, An isattached to a saturated carbon atom, e.g., the reaction of 4-hydroxy-7-methyl-l,8-naphthyridine-3-carboxylic acid with, 1,3- diiodopropane,l,6-di bromohexane or l,4-diiodo-2-butene to yield, respectively, 1,3-bis( 3-carboxy-7-methyl-4-oxol ,8- naphthyridyl-l )propane, 1,6-bis(3-carboxy-7-methyl-4-oxo- 1,8-naphthyridyl-l)hexane orl,4-bis(3-carboxy-7-methyl-4- alkyl ethoxymethylenemalonate, preferablythe diethyl ester,

to yield a dialkyl N-(2-pyridyl)amino methylenemalonate and thencyclizing this compound by heating it in an appropriate solvent, e.g.,diethyl phthalate, Dowtherm A (eutectic mixture of diphenyl and diphenylether), mineral oil, to obtain the intermediate lower-alkyl4-hydroxy-l,8-naphthyridine-3-carboxylate. To obtain the lower-alkyl7-acylamino-4-hydroxyl,8-naphthyridine-3-carboxylate one starts with the2,6- diaminopyridine and an acyl anhydride, preferably acetic anhydride,is included in the cyclizing step.

Also within the scope of the invention are salts of our above-describedl-substituted-4-oxol ,8-naphthyridine-3-carboxylic acids. Preferredtypes of salts are those having cations which do not increase thetoxicity of the compound as a whole toward animal organisms. Thesecomprise the alkali metal oxo-l,8-naphthyridyll )-2-butene. Othe'rbis-compounds encompassed by our invention are those where the twonaphthyridine rings are connected by a bis-ester grouping through the3-c'arboxy substituent, e.g., the bis-ester obtained by first reactingl-ethyl-7-methyl-4-oxo-l,8-naphthyridine-3- carboxylic acid withphosphorus oxychloride to form the corresponding 3-carboxylic acidchloride and then reacting two molar equivalents of the acid chloridewith a diol, e.g., 1,3- propanediol, l,4-dihydroxy-2-butene and1,6-hexanediol.

Our l-substituted-4-oxol 8-naphthyridine-3-carboxylic acids andderivatives have the further utility as intermediates in the preparationof other of our l-substituted-4-oxo-l,8- naphthyridine- 3-carboxylicacids and derivatives, as illustrated below for the preparation ofpreferred 7-substitutednaphthyridine embodiments.

For example, the 7-amino-4-oxo-l-substituted-l ,8-naphthyridine-3-carboxylic acids and derivatives are convenientlyconverted into the corresponding 7-diazonium salts which in turn areconverted into other 7-substituted-4-oxo-lsalts, e.g., the sodium orpotassium salts; the lower-alkaline earth metal salts, e.g., magnesiumor calcium salts; and, the ammonium or organic amine salts, e.g.,diethanolamine or N- methyl glucamine salts. Although medicinallyacceptable salts are preferred, other and all cationic salts are withinthe scope of our invention. All such salts, including those having toxiccations, are useful in characterizing the free acids and asintermediates in purification of the free acids. The salts are preparedfrom the acids using methods illustrated hereinbelow in the example.

Preferred ester embodiments of our 1-aubstituted-4oxol ,8-naphthyridine-3-carboxylic acids are those derived from alkanols havingup to 18 carbon atoms, phenols having up to 10 carbon atoms,(lower-tertiary-amino)-(polycarbon-lower-alkanols),(lowersecondary-amino)-(polycarbon-lower-alkanols). Other esterembodiments are the corresponding thiol esters prepared from thecorresponding alkylmercaptans, substituted-alkylmercaptansandthiophenols. These esters and their preparation are furtherillustrated in the examples hereinbelow. Although medicinally acceptableesters are preferred, other and all esters are encompassed by the scopeof the invention. All esters are useful in characterizing the free acidsand/or as intermediates in purification of the free acids.

Similarly, like the salts and esters, all amide and hydrazidederivatives are within the scope of the invention, and they have thesame utilities as the salts and esters. Preferred amide and hydrazideembodiments, which are prepared as illustrated in the examples, arethose derived from ammonia or hydrazine, unsubstituted or substituted byone or more lowmolec ular substituents, e.g., lower-alkyl,lower-hydroxyalkyl, lower-carboxyalkyl, lower-carbalkoxyalkyl,(lower-tertiaryamino )-(polycarbon-lower-alkyl), monocarbocyclic-aryl,and the like.

,tives, e.g., the corresponding 7-halo and 7-hydroxy compounds. The7-amino-4oxol-substituted-l ,8-naphthyridine- 3-carboxylic acids areprepared by reacting a lower-alkyl 7-acylarnino-4-hydroxy-l,S-naphthyridine-3-carboxylate, e.g., the ethyl7-acetylamino compound, with a Z-(aliphatic hydrocarbonating) agent,e.g., ethyl iodide orbenzyl chloride, to obtain the lower-alkyl7-acylamino-4-oxo-l-substituted- 1,8-naphthyridine-3-carboxylate, e.g.,the ethyl 7- acetylamino-4-oxo-l-(ethyl or benzyl)-l,8-naphthyridine-3-carboxylate, which is then hydrolyzed with an acidic agent, e.g., HCl toremove both the ester and N-acyl groups.

7-I-lydroxy-4-oxo- 1 -substituted- 1 ,8-naphthyridine-3 -carboxylicacids and derivatives are also useful as intermediates for preparationof the corresponding 7-halo compounds by their reaction with ahalogenating agent effective to convert hydroxy to halo, e.g.,phosphorus oxychloride, thionyl chloride, phosphorus trior pentachlorideto produce the corresponding 7-chloro compound or phosphorus tribromideto produce the 7-bromo compound.

' hydrazine, tertiary-aminoor secondary-amino-alkylamine,

sodium tertiary-aminoor secondary-amino-alkoxide. The 7- halo compoundalso can be catalytically reduced to remove the 7-halo substituent toyield the corresponding 7-unsubstituted-4-oxol-[Z-(aliphatic-hydrocarbyl) l ,8- naphthyridine-3-carboxylic acid andderivatives.

As pointed out above, the 4-oxo-l-substituted-l,8-naphthyridine-Ii-carboxylic acids are useful for the preparation oftheir salt, ester, amide and hydrazide derivatives using methods forconverting carboxylic acids into said derivatives. These methods areillustrated in the specific exemplary disclosure hereinbelow. Thesederivatives also have antibacterial and pharmacological properties, asillustrated in the specific examples below. v

The lower-alkyl esters of our 4-oxo-l-substituted-l,8-naphthyridine-B-carboxylic acids, especially methyl and ethyl esters,are'useful in their reaction with hydrazines and ammonia or amines tofonn the corresponding hydrazides and amides, respectively. Also, theycan be reacted with higher homologous alkanols, e.g.', n-butanol,1,3-dimethylhexariol, ndecanol, or with an aminoalcohol, e.g., 3-(1-piperidyl)propanol or 4-dimethylamino-butanol, by an ester exchangereaction to yield the corresponding higher alkyl or aminoalkyl ester,e.g., n-butyl, 1,3-dimethyl, hexyl, n-decyl, 3- (l-piperidyl)propyl or 4dimethylaminobutyl ester, respectively. Y a

4-Hydroxy-7-[2-(aryl)-ethenyl]-1,8-naphthyridine-3-carboxylic acids andderivatives are disclosed and claimed in our US. Pat. No.3,149,104,,issued Sept. 15, 1964. Compounds of this type can be preparedby reacting the corresponding lower-alkyl 4-hydroxy-7-methyl-l,8-naphthyridine-3-carboxylate with an aryl aldehyde, e.g.,benzaldehyde, or pyridine-2- aldehyde, in the presence of a mixture of alower-alkanoic acid and anhydride, e.g., acetic acid and aceticanhydride, preferably by heating in the range of about 100 C. to aboutthe free base and acid in an'organic solvent, in which case the saltseparates directly or can be obtained by concentration of the solution.

Although medicinally acceptable salts of said basic compounds arepreferred, all acid-addition salts are within the scope of ourinvention. All acid-addition salts are useful as sources of the freebase form even if the particular salt per se is desired only as anintermediate product as for example 150 C., thereby yielding thecorresponding lower-alkyl 4- hydroxy-7-[ 2-( aryl)-ethenyl]- l,8-naphthyridine-3-carboxylate, e.g., the corresponding7'-(2-phenyl-ethenyl) (i.e., 7- styryl) or 7-[2-(2-pyridyl)ethenyl]ester. The corresponding acid is obtained by saponification of the esterand, in turn, can be converted into other esters or salt, amide orhydrazine derivatives, e.g., those defined hereinabove for ourl-substituted-4-oxol ,8-naphthyridine-3-carboxylic acids.

Our 4-oxol substituted-l ,8-naphthyridine-3-carboxylic acids andderivatives when containing a basic moiety, i.e., a lower-tertiaryorsecondary-amino moiety, for example, a 2- diethylaminoethyl ester, al-[3-( l-piperidyl)propyl] compound or a 7-(4-n-propylamino-butoxyl)compound, are useful both in the free base form and in theform ofacid-addition salts; and both forms are within the purview of theinvention, and, in fact, are considered to be one and the sameinvention. The acid-addition salts are simply a more convenient form foruse; and in practice, use of the salt form inherently amounts to use ofthe base form. The acids which can be used to prepare the acid-additionsalts include preferably those which produce, when combined with thefree base, medicinally acceptable salts, that is, salts whose anions arerelatively innocuous to the animal organism in medicinal doses of thesalts, so that the beneficial physiological or antibacterial propertiesinherent in the free base are not vitiated by side effects ascribable tothe anions. ln practicing our invention, we found it convenient to formthe hydrochloride salts. However, other appropriate medicinallyacceptable salts within the scope of theinvention are those derived frommineral acids such as hydrobromic acid, hydriodic acid, nitric acid,phosphoric acid, sulfamic acid, and sulfuric acid; and organic acidssuch as acetic acid, citric acid, tartaric acid, lactic acid,methanesulfonic acid, 'ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, quinicacid, and the like, giving thehydrobromide, hydriodide, nitrate, phosphate, sulfarnate,

acetate, citrate, tartrate, lactate, methanesulfonate, ethanesul-'fonate, benzenesulfonate, p-toluenesulfonate and quinate, respectively.v

The acid-addition salts of said basic compounds are prepared either bydissolving the free base in aqueous or aqueous-alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting when the salt is formed only for purposesof purification or identification, or when it is used as an intermediatein preparing a medicinally acceptable salt by ion exchange procedures.Also encompassed by our invention are quaternary-ammonium salts of theaforesaid compounds containing a lowertertiary-amino moiety. These saltsare useful for further identification of the aforesaid tertiary-aminocompounds. The quaternary ammonium salts are obtained by the addition ofesters having a molecular weight less than about 200 to the free baseform of the compounds. vA preferred class of esters comprises alkyl,alkenyl or aralkyl esters of inorganic acids or organic sulfonic acids,and include such compounds as methyl chloride, methyl bromide, methyliodide, ethyl bromide, propyl chloride, 2-hydroxyethyl bromide, ally]chloride, allyl bromide, methyl sulfate, methyl benzenesulfonate, methylptoluenesulfonate, benzyl chloride, benzyl bromide, and substitutedbenzyl halides, such as p-chlorobenzyl chloride, pnitrobenzyl chloride,o-chlorobenzyl chloride, p-rnethoxybenzyl chloride, and the like. Thequaternary ammonium salts are prepared by mixing the free base and thealkyl, alkenyl or aralkyl esters in an organic solvent inert under theconditions of reaction, for example, ethanol, methanol, ether,acetonitrile and the like. Heating can be used to facilitate thereaction, although salt formation usually takes place readily at roomtemperature. The quaternary ammonium salt separates directly or can beobtained by concentration of the solution.

The molecular structures of the final products and intermediates of ourinvention are established by their mode of synthesis and confirmed bythe correspondence of calculated and found values for the elementaryanalyses for representative examples and by infrared, ultraviolet andNMR spectral analyses.

Our l-[Z-(aliphatic-hydrocarbyl) ]-4-oxo- 1,8-

naphthyridine-3-carboxylic acids and derivatives when tested accordingto standard in vitro bacteriological evaluation procedures possessantibacterial activity, for example, against organisms such asStaphylococcus aureus, Eberthella typhi, Clostridium welchii, asillustrated below in the examples. Preferred embodiments also were foundto have significant in vivo activity against gram-negative bacteria,e.g., Klebsiella pneumoniae, Salmonella typhimurium, in mice whenadministered orally and/or subcutaneously at dose levels in the range ofabout to 400 mg./kg./d. Embodiments were found to increase thehexobarbital-induced sleeping time in mice when administeredintraperitoneally forty minutes before intraperitoneal administration of40 mg./kg. of hexobarbital. Results in the following examples are givenin terms of the number of animals caused to exhibit a loss of rightingreflex for 1 minute or more at a given dose level, e.g., 200 mg./kg., orin terms of ED,, i.e., the effective dose in mgJkg. that caused 50 percent of the animals to exhibit a loss of righting reflex for 1 minute ormore. Positive results in this barbital-potentiating test indicate thecompound tested has central nervous system depressant activity and isuseful as a potentiator for barbiturates.

The following examples will further illustrate the invention without,however, limiting it thereto.

EXAMPLE 1 acid, 1

water was refluxed until the solids dissolved. To this solution wasadded 28 cc. of ethyl iodide and the resulting mixture was refluxed fordays. The reaction mixture was cooled in an ice bath; and the resultingprecipitate was collected, recrystallized from acetic acid, washed withwater and dried in a vacuum oven (at about 70 C.) to yield 8.7 g. (66percent yield) of the crystalline product, l-ethyl-7-methyl-4-oxo-l,8-naphthyridine-3-carboxylic acid, m.p. 226.8-230.2 C. (com).

Anal. Calcd. for c,,n,,N,o,= C, 62.05; H, 5.21; N, 12.06;

N.E. (neutral equivalent), 232.

Found: C, 62.12; H, 5.47; N, 11.92; NE, 229.

The foregoing preparation was carried out using a shorter reactionperiod as follows: A warm solution containing 41 g. of4-hydroxy-7-methy1-1,8-naphthyridine-3-carboxylic acid and 39 g. ofpotassium hydroxide in 1 liter of ethanol and 200cc. of water wastreated with 50 cc. of ethyl iodide and the resulting mixture wasrefluxed gently overnight, acidified with hydrochloric acid and cooled.The resulting precipitate was collected and recrystallized twice fromacetonitrile to yield 26 g. (56 percent yield) ofnaphthyridine-3-carboxylic acid, m.p. 229230 C.

1 -Ethyl-7-methy1-4-oxo- 1 ,8-naphthyridine-3-carboxylic acid whentested according to standard in vitro bacteriological evaluationprocedures was found to possess antibacterial activity, for example, asfollows:

Log Reciprocal Minimum l -Ethyl-7-methyl-4-oxol,8-naphthyridine-3-carboxylic acid was found to have significant in vivoactivity against Kleb- .riella pneumoniae in mice when administeredorally or subcutaneously at dose levels as low as 100 mg./kg./d. and,also, against Salmonella typhimurium in mice when administeredsubcutaneously at dose level as low as 100 mg./kg./d. This compound whentested according to the procedure described hereinabove for potentiationof hexobarbital sleeping time in mice was found to have an ED of lessthan 50 mg./kg. This same compound was found to have an acute oraltoxicity (LD in mice of 4,000 mg./kg. after'24 hours and 3,300 i 975after 7 days and an acute subcutaneous toxicity (LD in mice of 500 i 52mg./kg'.

EXAMPLE 2 Sodium l-ethyl-7-methyl-4-oxol ,8-naphthyridine-3-carboxylatewas prepared by warming on a steam bath a mixture of 6.9 g. ofl-ethyl-7-methyl-4-oxo-l,8-naphthyridine-3-carboxylic acid, 1.1 g. ofsodium hydroxide and 150 cc. of

ethanol until dissolution resulted. The warm solution was fil- EXAMPLE 3Calcium l-ethyl-7-rnethyl-4-oxol ,8-naphthyridine-3-carboxylate wasprepared as follows: To a solution containing 12 g. ofl-ethyl-7-methyl-4-oxo-1 ,8-naphthyridine-3-carboxylicl-ethyl-7-methyl-4-oxo- 1 ,8-

acid, 25 cc. of 10 percent aqueous potassium hydroxide solution and 300cc. of water was added with stirring a solution containing 30 g. ofcalcium acetate dihydrate. The reacn'on mixture was stirred at roomtemperature for about 10 minutes; and the resulting precipitate wascollected, washed with water and air-dried. The solid was recrystallizedonce from methanol-water (4:1), a second time from methanohwater (5:1),and then air-dried to yield 5.5 g. of calcium di-( l-ethyl-7-methyl-4-oxo-1 ,8-naphthyridine-3-carboxylate m.p. 300 C. (corr.

Anal. Calcd. for C H CaN,O C, 57.40; H, 4.40; N, 1 1.14.

Found: C, 57.16; H, 4.67; N, 11.35.

Calcium di-( 1-ethyl-7-methyl-4-oxo-l ,8-naphthyridine-3- carboxylate)was found to have significant in vivo activity against Klebsiellapneumoniae in mice when administered orally at a dose level as low asmg./kg./d. This same compound when tested according to the proceduredescribed hereinabove for potentiation of hexobarbital sleeping time inmice was found to have an ED, of i 20 mg./kg.

EXAMPLE 4 1 ,7-Dimethyl-4-oxo- 1 ,8-naphthyridine-3-carboxy1ic acid wasprepared following the procedure described in Example 1 using 20.4 g. of4-hydroxy-7-methy1-1,8-naphthyridine-3-carboxylic acid, 49 g. ofpotassium hydroxide, 400 cc. of ethanol, cc. of water, 55 cc. of methyliodide and a reflux period of 5 days. The reaction mixture was cooled inan ice bath and the solid that separated was collected, washed twicewith acetone and dried in a vacuum oven (about 70 C.). The solid wasdissolved in water, boiled with decolorizing charcoal and filtered. I

EXAMPLE 5 I 7-Methyl-4-oxol -n-pr0pyl- 1 ,8-naphthyridine-3 -carboxylicacid was prepared following the procedure described in Example 1 using20.4 g. of 4-hydroxy-7-methyl-l,8-naphthyridine- 3-carboxylic acid, 19.5g. of potassium hydroxide, 400 cc. of ethanol, 140 cc. of water, 40 cc.of n-propyl iodide and a reflux period of 6 days. The reaction mixturewas cooled and the solid that separated was collected and recrystallizedfrom ethanol to yield 17.7 g. (72 percent) of7-methyl-4-oxo-l-npropyl-l,8-naphthyridine-3-carboxylic acid, m.p.209.4-2 10.2 C. (cor-L).

Anal. Calcd. for C, H, N O C, 63.40; H, 5.73; N, 11.38.

Found: C, 63.67; H, 5.87; N, 11.25.

7-Methy1-4-oxol -n-propyl-1 ,8-naphthyridine-3-carboxylic acid whentested according to standard in vitro bacteriological evaluationprocedures was found to possess antibacterial activity, for example, tohave Bs and Be values, respectively, of 4.3 and 3.0 againstStaphylococcus aureus, of 5.0 and 3.6 against Eberthella typhi and of5.0 and 4.0 against Clostridium welchii. This same compound was found tohave significant in vivo activity against Klebsiella pneumoniae in micewhen administered orally or subcutaneously at a dose level as low as 100mg./kg./d. and, also, against Salmonella typhimurium in mice whenadministered orally at a dose level as low as 200 mg./kg./d.

11 EXAMPLE 6 .ice bath and the resulting precipitate was collected,washed with acetone and recrystallized twice from ethanol to yield about14 g. of the product, l-n-butyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 220.4222.0 C. (corr.).

Anal. Calcd. for c,,H,,N,0,; N, 10.77; N.E., 260.

Found: N, 10.69; NE, 258.

l-n-Butyl-7-methyl-4-oxo-.l ,8-naphthyridine-3-carboxylic acid whentested according to standard in vitro bacteriological evaluationprocedures was found to possess antibacterial activity, for example, tohave'Bs and Bo values (as defined hereinabove) of 3.6 and 3.12 againstEberthella typhi.

EXAMPLE7 l -1sobutyl-7-methyl-4-oxo-1 ,8-naphthyridine-3-carboxylic acidwas prepared following the procedure described in Example 1 using 20.4g. of 4-hydroxy-7-methyl-l,8-naphthyridine- 3-carboxylic acid, 24.5 g.of potassium hydroxide, 400 cc. of ethanol, 140 cc. of water, 45 cc. ofisobutyl iodide and a reflux period of 8 days. The reaction mixture waschilled in an ice bath and the solid that separated was collected. Thefiltrate was acidified with hydrochloric acid, the mixture chilled in anice bath, and the resulting precipitate collected. The two solidportions were combined and recrystallized three times from acetic acidto yield 7.8 g. of 1-isobutyl-7-methyl-4-oxo-l,8-naphthyridine-3-carboxylic acid, m.p. 234.8236.8 C.

(corr.). 1

Anal. Calcd. for C H N O N, 10.68; N.E., 268.

Found: N, 10.77; N.E'., 260.

lIsobutyl-7-methyl-4-oxo-l ,8-naphthyridine-3- carboxylic acid whentested according to standard in vitro bacteriological evaluationprocedures was found to possess antibacterial activity, for example, tohave Bs and Be values, respectively, of 4.3 and 3.6 againstStaphylococcus aureus, of 4.3 and 3.3 against Eberthella typhi and 4.6and 3.0 against Clostridium welchii. This same compound when tested asdescribed above was found to potentiate hexobarbital sleeping time inthree out of six mice at a dose level of 200 mg./kg.

EXAMPLE 8 7-Methyl-4-oxo- 1 -n-pentyl- 1 ,8-naphthyridine-3-carboxylicacid was prepared following the proceduredescribed in Example 1 using20.4 g. of 4-hydroxy-7methyl-l,8-naphthyridine- 3-carboxylic acid, 19.5g. of potassium hydroxide, 400 cc. of ethanol, 140 cc. of water, 40 cc.of n-pentyl iodide and a reflux period of 5 days. The reaction mixturewas cooled in an ice bath and the resulting precipitate was collectedand recrystallized twice from isopropyl alcohol, the second time usingdecolorizing charcoal. There was thus obtained 4.1 g. of7-methyl-4-oxo.- 1 -n-pentyll ,8-naphthyridine-3-carboxylic acid, m.p.171.4-l72.8 C. (corr.).

Anal. Calcd. for C, -,H, N O C, 65.69; H, 6.62; N, 10.28.

Found: C, 66.01; H, 6.57; N, 10.15.7Methyl-4-oxo-l-npentyl-1,8-naphthyridine-3- carboxylic acid when testedaccording to standard in vitro bacteriological evaluation procedures wasfound to possess antibacterial activity, for example, to have Bs and Bcvalues, respectively, of 4.12 and 3.12 against Staphylococcus aureus andof 4. l 2 and 3.3 against Clostridium welchii.

EXAMPLE 9 1-n-Hexyl-7-methyl-4oxo-- 1,8-naphthyridine-3- carboxylic acidwas prepared following the procedure described in Example 1 using 20.4g. of 4-hydroxy-7-methyl-l,8-naphthyridine- 3-carboxylic acid, 19.5 g.of potassium hydroxide, 400 cc. of ethanol, 140 cc. of water, 40 cc. ofn-hexyl iodide and a reflux period of 5 days. The reactionmixture (pH6.4) was made more acidic with concentrated hydrochloric acid andchilled in an ice bath. The resulting precipitate was collected andrecrystallized twice from isopropyl alcohol, the second time usingdecolorizing charcoal. There was thus obtained 8.6 g. of the product,1n-hexyl-7-methyl4-oxo-l,8-naphthyridine-3- carboxylic acid, a paleyellow solid, mp 146.2-l48.2 C. (corr.).

Anal. Calcd. for G l-1 N 0 C, 66.64; H, 6.99N, 9.72.

Found: C, 66.93; H, 6.88; N, 9.60.

EXAMPLE l0 Ethyl l-ethyl-7-methyl-4-oxo-l ,8-naphthyridine-3-carboxylatewas prepared as follows: A 6.9 g. portion of sodium was dissolved in 300cc. of absolute ethanol (to produce a solution of sodium ethoxidemethanol) and to the resulting solution was added 23.2 g. of ethyl4-hydroxy-7-methyl-1,8- naphthyridine-3-carboxylate. The reactionmixture was brought to reflux on a steam bath and to the resultingsuspension was added 35 cc. of ethyl iodide. The resulting reactionmixture was refluxed for 16 hours and chilled in an ice bath; and, whenno solid separated, it was evaporated to about onethird its volume on asteam bath under reduced pressure, acidified, diluted and shaken wellwith four volumes of water, and filtered. The solid that separated fromthe filtrate was collected and recrystallized three times from ethylacetate, the second time using decolorizing charcoal. There wasthusobtained 7.0 g. of the product, ethyl 1-ethy1-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. l20.8-121.6 C. (corr.

Anal. Calcd. for C H N O z C, 64.60; H, 6.19; N, 10.77.

Found: C, 64.58; H, 6.03; N, 10.93.

Ethyl 1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate was foundto have significant in vivo activity against Klebsiella pneumoniae inmice when administered orally or subcutaneously at dose levels as low asmg./kg./d.

EXAlVlPLE II n-Butyl l-ethyl-7-methyl-4-oxo- 1,8-naphthyridine-3-carboxylate was prepared as follows: A mixturecontaining 13 g. of ethyl l-ethyl-7-methyl-4-oxo-l,8-naphthyridine-3-carboxylate, 25 cc. of n-butanol and 0.3 g. of sodiummethoxide was heated in an oil bath at about l22-125 C. for a period of48 hours. The reaction mixture was then cooled, filtered, and thefiltrate concentrated in vacuo to remove the solvent. The remainingreaction mixture solidified on cooling. The solid was collected andrecrystallized from cyclohexane using decolorizing charcoal. Theair-dried product, n-butyl l-ethyl- 7-methyl-4-oxo- 1,8-naphthyridine-3-carboxylate, m .p. 98,0-99.4 C. (corr.), weighed 8.8g. (61 percent yield).

Anal. Calcd. for C,,,H,,N,0,= C, 66.66; H, 6.98; N, 9.71.

Found: C, 66,49; H, 6.72; N, 9.64.

EXAMPLE l2 1,3-Dimethylbutyl l-ethyl-7-methyl-4-oxo l ,8-naphthyridine-3-carboxylate was prepared as follows: A mix turecontaining 11 g. of ethyl 1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate, 25 cc. of 4-methyl-2-pentanol and 0.1 g. ofsodium methoxide was heated for about 16 hours in an oil bath kept atabout -135 C. The reaction mixture was cooled, filtered, andconcentrated in vacuo to remove the solvent. The resulting solidifiedreaction mixture was recrystallized twice from cyclohexane, once fromdi-isopropyl ether, washed with n-pentane and dried in vacuo at 70 C. toyield 6.5 g. of product, 1,3-dimethylbutyl 1-ethyl-7-methyl-4-oxo-l,8-naphthyridine-3-carboxylate, m.p. 114.6-119.4 C. (corr.).

Anal-Calcd. for c H N O z C, 68.36; H, 7.64; N, 8.84.

Found: C, 68.68; H, 7.25; N, 8.87.

EXAMPLE 13 Ethyl l-ethyl-4-oxo-7-styryl 1 ,8-naphthyridine-3-carboxylatewas obtained together with the corresponding carboxylic acid in thefollowing synthesis: A mixture containing 64 g. of ethyl4-hydroxy-7-styryl-l,8-naphthyridine-3-carboxylate, 52 g. of potassiumhydroxide, 920 cc. of ethanol, 320 cc. of water, and 80 cc. of ethyliodide was refluxed for about 16 hours. The acidic reaction mixture wascooled in an ice bath; and the resulting precipitate was collected,washed twice with acetone and dried to yield 39.0 g. of solid (seebelow). The acetone washings were diluted with water and the yellowprecipitate that separated was collected, washed with boiling water,recrystallized once from acetic acid-water and a second time fromabsolute ethanol to yield 6.1 g. of ethyl l-ethyl-4-oxo-7-styryl-1,8-naphthyridine-3-carboxylate, m.p.' 174.2-l 766 C.(corr.).

Anal. Calcd. for C l-1 N C, 72.39; H, 5.79; N, 8.04.

Found: C, 72.15; H, 5.49; N, 8.30.

The above 39 g. of solid was washed with hot percent aqueous potassiumcarbonate solution and the resulting suspension was acidified withhydrochloric acid and filtered.

The filtered product was washed with water and dried in an oven (70 C.)to yield about 39 g. (62 percent) of l-ethy1-4- oxo-7-styryll,S-naphthyridine-3-carboxylic acid.

EXAMPLE l4 1Ethyl-4-oxol ,8-naphthyridine-3,7-dicarboxylic acid wasprepared as follows: To a stirred suspension con-taining 28.0 g. ofl-ethyl-4-oxo-7-naphthyridine-3-carboxylic acid in 192 cc. of pyridineand 35 cc. of water cooled to l5-20 C. in an ice bath was addedportionwise over a period of about 1 hour 36.8 g. of potassiumpermanganate. The temperature was kept at 20 C. during the addition ofthe permanganate. After two 90 cc. portions of water were added to thereaction mixture, one after half of the permanganate had been added andthe other after completion of the addition of the permanganate, thereaction mixture was stirred for an additional 30 minutes. After anunsuccessful attempt to remove the colloidal manganese dioxide byfiltration, sodium bisulfite solution was added until all manganesedioxide had been destroyed. The mixture was than acidified with 6Nsulfuric acid whereupon pale yellow solid separated. The solid wascollected and dissolved in 10 percent aqueous potassium carbonatesolution. This solution was filtered and to the filtrate was addedhydrochloric acid to reprecipitate the product. The solid was collected,washed with water and recrystallized from acetic acid using decolorizingcharcoal. lt was then washed with acetone and dried in a vacuum oven at70 C. to yield 5 g. (77 percent) of the product, l-ethyl-4-oxo-l,8-naphthyridine- 3,7-dicarboxylic acid, m.p. 282-283.4 C. (com) withdecomposition.

Anal. Calcd. for C H N O N, 10.68; NE. 131 and 262.

Found: N, 10.76; N.E., 129 and 273.

Using a molar equivalent quantity of ethyl l-ethyl-4-oxo-7- styryl- 1,8-naphthyridine-3-carboxylate in the above oxidation in place of thecorresponding acid, there was obtained ethyl 1- ethyl-7-carboxy-4-oxol,8-naphthyridine-3-carboxylate, mp. 24 1-243 C.

EXAMPLE l5 Ethyl 7-carboxyl -ethy1-4-oxo-l,S-naphthyridine-Ii-carboxylate was prepared as follows: A 60 gramportion of ethyl 1- ethyl-4-oxo-7-styryl l,8-naphthyridine-S-carboxylate was suspended in a mixture of 380 cc. ofpyridine and 66 cc. of water. The mixture was cooled to 10 C. and to itwas added with stirring in small portions over a period of 90 minutes85.5 g. of potassium permanganate. The temperature of the reactionmixture was kept at l0l5 F. using an ice bath. At 30 minute intervals110 cc. portions of water were added to facilitate stirring. Stirringwas continued for an additional hour after all of the potassiumpermanganate had been added.

The reaction mixture was then allowed to stand overnight allowing thetemperature to rise to room temperature. The precipitated manganesedioxide was filtered off and washed with water. The filtrate andwashings were combined and acidified with concentrated hydrochloric acidto yield a pale yellow precipitate. The mixture was cooled overnight ina cold room; and the precipitate was then collected, washed with alittle water, washed with acetone, and air-dried to yield 33.9 g. (68percent yield) of the product, ethyl 7-carboxy-l-ethyl-4- 0x0- 1,8-naphthyridine-3-carboxylate, mp. 24 l -243 C.

EXAMPLE l6 Ethyl 7-carboethylmercaptol -ethyl-4-oxol ,8naphthyridine-S-carboxylate was prepared as follows: To a suspension of10.0 g. of ethyl 7-carboxyl-l-ethyl'4-oxo-l,8-naphthyridine-lcarboxylate in 200 cc. of chloroform was added 4.8 g. ofoxalyl chloride and the resulting mixture was refluxed on a steam bath.An additional 2.2 g. portion of oxalyl chloride was added after 15minutes and again after 10 more minutes for a total of 9.2 g. of thisreactant. Refluxing was continued for 5 minutes more, the reactionmixture cooled slightly, and 20 g. of ethyl mercaptan added. The mixturewas stirred and allowed to stand at room temperature overnight. A smallamount of insoluble material was filtered off and the filtrate wasevaporated to dryness on steam bath to yield a brown solid residue whichwas washed well with ether, dried, and recrystallized from ethyl acetate(about 200 cc.) using decolorizing charcoal and dried at C. for 2 hoursto yield 6.3 g. of the product, ethyl 7-carboethylmercapto-1-ethyl-4-oxol ,8-naphthyridine-3-carboxylate, m.p. 189.2-l 90.8 C.(corr.).

Anal. Calcd. for C H N O S: N, 8.38: S, 9.59.

Found: N, 8.49; S, 9.71.

EXAMPLE 1? Ethyl l-ethyl-7-hydroxymethyl-4-oxol ,8-naphthyridine-3-carboxylate was prepared as follows: A mixture containing 3.3 g. ofethyl 7-carboethylmercapto-l-ethyl-4-oxo-1,8-naphthyridine-3-carboxylate, 20 g. of Raney nickel and cc. of ethanolwas refluxed on a steam bath with stirring for 3 days. The reactionmixture was filtered through a sintered glass funnel to remove thenickel catalyst; the catalyst rinsed with fresh ethanol; and thecombined ethanol washings and filtrate from the reaction mixture wereevaporated to dryness on a steam bath. The remaining residue wastriturated with a small amount of ethyl acetate and the solid thatformed was collected, washed with cold ethyl acetate and air-dried. Thissolid material was then boiled with ethyl acetate and the hot mixturefiltered; most of the solid did not dissolve. The filtrate on coolingyielded a crystalline product which was recrystallized again from ethylacetate to yield a small quantity of the desired product, ethyll-ethyl-7-hydroxymethyl-4-oxo-l ,8- naphthyridine-3-carboxylate, m.p.l73.5-174.0 C.

Anal. Calcd. for C I-1 N 0 N, 10.14; C, 60.86; H, 5.84.

Found: N, 10.19; C, 61.14; H, 5.52.

EXAMPLE l8 l-Ethyl- 7-hydroxymethyl-4-oxol ,8-naphthyridine-3-carboxylicacid was prepared by hydrolyzing its ethyl ester as follows: A mixtureof a small portion of the ethyl ester and 5 percent aqueous potassiumhydroxide was boiled for 2 to 3 minutes, after which time the ester haddissolved; boiling was continued for another 2 minutes and the reactionmixture was allowed to cool slowly. The cooled solution was madeslightly acidic with 6N hydrochloric acid. The white precipitate wascollected, washed successively with water and acetone, recrystallizedfrom absolute ethanol, and air-dried to yield the desired product,1-ethy1-7-hydroxymethyl-4-oxo-l ,8- naphthyridine-3-carboxylic acid, mp.25 8-260 C.

Anal. Calcd. for C I-1 N 0 C, 58.06; H, 4.87, N, 11.29.

Found: C, 57.98; H, 4.94; N, 11.33.

EXAMPLE 19 7-Acetoxymethyll -ethyl-4-oxol ,8-naphthyn'dine-3-carboxylicacid was prepared by acylating the corresponding 7- hydroxymethylcompound as follows: A mixture containing 10.0 g. of1-ethyl-7-hydroxymethyl-4-oxo l ,S-naphthyridine- 3carboxylic acid, 8.2g. of acetic anhydride and 50 cc. of pyridine was warmed on a steam bathfor 1 hour. The reaction mixture was then poured into a mixture of iceand water with stirring followed by addition of cc. of acetic acid. Themixture was stirred; and the precipitate was collected, recrystallizedtwice from isopropyl alcohol and dried in vacuo at 70 C. for 7 hours toyield 8.0 g. of the product, 7-acetoxymethyl-1- ethyl-4-oxol,8-naphthyridine-3-carboxylic acid, m.p. 169.8- l71.6 C. (corn);

Anal. Calcd. for C H N O z C, 57.93; H, 4.86; N, 9.65.

Found: C, 57.63; H, 4.84; N, 9.79.

7Acetoxymethyll -ethyl-4-oxol ,8-naphthyridine-3-carboxylic acid wasfound to have significant in vivo activity 1 against Klebsiellapneumoniae, Escherichia coli and Salmonella typhimurium in mice whenadministered orally at respective dose levels of 50, 50 and 100mg./kg./d.

EXAMPLE 20 7-( Diethylaminoacetoxymethyl)- l -ethyl-4-oxol ,8-naphthyridine-B-carboxylic acid was prepared as follows: A mixturecontaining 7.0 g. of 7-chloroacetoxymethyl-1-ethyl-4-oxo-l,8-naphthyridine-3-carboxylic acid, 20 cc. of diethylamine and 100cc. of ethanol was refluxed gently on a steam bath for 3 hours and thenevaporated to dryness in vacuo. The remaining solid material was takenup in water; the aqueous mixture filtered; and the filtrate acidifiedwith acetic acid. The resulting precipitate was collected,recrystallized successively from isopropyl alcohol and acetic acid,washed with acetone and air-dried to yield 2.5g. of the product, 7-(diethylaminoacetoxymethyl)- l -ethyl4-oxol ,8-naphthyridine-3-carboxylic acid, m.p. 249.8255.0 C. (corn).

Anal. Calcd. for C, H N O C, 59.82; H, 6.42; N, l 1.62.

Found: C, 69.75; H, 6.52; N, 11.49.

7-( Diethylaminoacetoxymethyl)- l -ethyl-4-oxo-1 ,8-naphthyridine-S-carboxylic acid was found to have significant in vivoactivity against Klebsiella pneumoniae in mice when administered orallyat a dose level of 100 mg./kg./d.

The intermediate7-chloroacetoxymethyl-1-ethyl-4-oxol,8-naphthyridine-3-carboxylic acidwas prepared as follows: A mixture containing 17.4 g. of1-ethyl-7-hydroxymethyl-4- oxo-l,8-naphthyridine-3-carboxylic acid, 24.0g. of chloroacetic anhydride and 150 cc. of acetic acid was heated on asteam bath with stirring for 3 hours and then poured into 2 liters ofwater with stirring. The solid precipitate was collected andrecrystallized from isopropyl alcohol to yield 7- chloroacetoxymethyll-ethyl-4-oxo-l ,8-naphthyridine-3-carboxylic acid, m.p. l59l63 C., whichwas used in the above reaction without further recrystallization.

EXAMPLES 2 l23 The 7-hydroxymethyll -substituted-4-oxol ,8-naphthyridine-3-carboxylic acids of Table A below can be preparedfollowing the procedures of Examples 16, 17 and 18 using molarequivalent quantities of the corresponding ethyl 7-carboxy-4-oxo1-substitutedl ,8-naphthyridine-3-carboxylate in place of ethyl7-carboxy-l-ethyl-4-oxo-1,8- naphthyridine-3-carboxylate, to preparefirst the corresponding ethyl 7-carboethylmercaptolsubstituted-4-oxo-l,8naphthyridine-3-carboxylate, then the corresponding ethyl 7- 16hydroxymethyl- 1 -substituted-4-oxol ,8-naphthyridine-3-carboxylate, andfinally the corresponding 7-hydroxymethyl-1- substituted-4-oxo- 1,8-naphthyridine-3-carboxylate, and finally the corresponding7-hydroxymethyl-l-substituted-4- oxo-l,S-naphthyridine-B-carboxylicacid.

C 0 O H Ex. No. M.P., C.

21 CH CH CH 208.5-210 22 (CH CH 170-1 7 l .5 23 CH 295- 320 phimun'umand Proteus rettgeri in mice when administered orally at respective doselevels of 50, 400 and 200 mg./kg./d. This same compound when tested asdescribed hereinabove as found to potentiate hexobarbital sleeping timein four out of 10 mice at a dose level of 100 mg./kg.

EXAMPLE 24 4-Ox0-1 -n-propyl-l ,8-naphthyridine-3,7-dicarboxylic acidwas prepared as follows: A mixture containing lg. of 7-hydroxymethyl-4-oxo- 1 -n-propyl- 1 8-naphthyridine-3-carboxylic acid, 2g. of potassium permanganate, 100 cc. of water and about 60 drops of 10percent aqueous potassium hydroxide solution as stirred for 2 hours. Theexcess potassium permanganate was st reduced using sodium bisulfite. Theprecipitate of manganese dioxide was filtered off and washed with water.The filtrate and washings were combined and acidified with hydrochloricacid. The resulting precipitate was collected and recrystallized fromethanol to yield the product,4-oxo-l-n-propyl-1,8-naphthyridine-3,7-dicarboxylic acid, m.p. 251.2252.2 C. (corn). I

Anal. Calcd. for C, H, N O C, 56.52; H, 4.38; N, 10.14; 0,

28.96. Found: C, 56.53; H, 4.19; N, 10.32; 0, 28.96.

EXAMPLE 25 7-Acetoxymethyll-n-propyl-4-oxo- 1 ,8-naphthyridine-3-carboxylic acid was prepared as follows: A mixture containing 2.12 g. of7-hydroxymethyl-ln-propyl-4-oxo-l,8- naphthyridine-3-carboxylic acid, 50cc. of acetic anhydride and 40 cc. of pyridine was allowed to stand forminutes. The reaction mixture was added to a mixture of ice and coldwater and allowed to stand overnight in a refrigerator. The resultingwhite solid was collected, washed successively with water and a smallamount of ether, and recrystallized from ethanol to yield 1.95 g. of theproduct, m.p. 149.2-l50.4 C. (corn).

Anal. Calcd. for C, -,H N,O,,: C, 59.20; H, 5.30; N,9.20.

Found: C, 59.36; H, 5.36; N, 9.32.

7-Acetoxymethyl- 1 -npropyl-4-oxo- 1 ,8-naphthyridine-3 carboxylic acidwas found to have significant in vivo activity against Klebsiellapneumoniae and Escherichia coli in mice when, administered orally atrespective dose levels of 200 and mg./kg./d.

1. EXAMPLE 26.

7-Dichloroacetoxymethyll -ethyl-4-o'xol ,8-naphthyridine- 3-carboxylicacid was prepared as follows: A mixture of 1-ethyl-7-hydroxymethyl-4-oxo-l ,8-naphthyridine-3-carboxylic acid and cc.of dichloroacetic anhydride was placed in a warm water bath for about 15minutes and then poured into ice water whereupon a yellow oil separated.The water was decanted and the oil washed once with water whereupon itsolidified. The solid was then recrystallized from ethanol, usingdecolorizing charcoal, to yield 3.2 g. of the product, 7-dichloroacetoxymethyl-l-ethyl-4-oxo-1,8-naphthyridine-3- carboxylicacid, m.p. 133.0-139.4 C. (corr.

Anal. Calcd. for C H, Cl,N,O N, 7.80; C, 19.75.

Found: N, 8.09; C, 19.41.

7-Dichloroacetoxymethyl- 1-ethyl-4-oxol ,8-naphthyridine- 3-carboxylicacid was found to have significant in vivo activity against Klebsiellapneumoniae in mice when administered orally at a dose level of 200mg./kg./d.

EXAMPLE 27 7-Isobutyroxymetl1yll -ethyl-4-oxo-l ,8-naphthyridine-3-carboxylic acid was prepared as follows: A mixture containing 2 g. of l'-e'thyl-7-hydroxymethyl-4-oxo-l,8-naphthyridine-3- carboxylic acid,about 8 cc. of isobutyric anhydride and about 50 cc. of pyridine waswarmed in a water bath for about 3 hours. The reaction mixture waspoured onto crushed ice and the resulting precipitate was collected andrecrystallized from ethanol to yield 1.47 g. of the product,7-isobutyroxymethy1-1- ethyl-4-0xol ,8-naphthyridine-3-carboxylic acid,m.p. 139.2-141.2C.(corr.).

Anal. Calcd. for C,,H,,,N,0,. C, 60.37; H, 5.70; N, 8.80.

Found: C, 60.13; H, 5.74; N, 8.61.

7-lsobutyroxymethy1-1-ethyl-4-oxo-1 ,8-naphthyridine-3- carboxylic acidwas found to have significant in vivo activity against Klebsiellapneumoniae in mice when administered orally at 200 mg./kg./d.

EXAMPLE 28 1-Ethyl-4-oxo-7-succinoxymethyl- 1,8-naphthytidine-3-carboxylic acid was prepared as follows: A mixturecontaining 2 g. of l-ethy1-7-hydr0xymethyl-4-oxo- 1,8-naphthyridine-3-carboxylic acid, 1.5 g. of succinic anhydride andabout 50 cc. of pyridine was warmed on a water bath for about 3 hoursand then poured onto crushed ice. The resulting mixture was made acidicto litmus using hydrochloric acid, and the precipitate that separate wascollected and recrystallized from water to yield 2.15 g. of the product,l-ethyl-4-0xo-7succinoxymethyl- 1,8-naphthyridine-3-carboxylic acid,m.p. 145.8-l48.2 C. (corr.).

Anal. Calcd. for C l-1 N 0 C, 55.17; H, 4.63; N, 8.04.

Found: C, 55.1 1; H, 4.53; N, 8.11.

l-Ethyl-4-oxo-7-succinoxymethyl-1 ,8-naphthyridine-3-carboxylic acid wasfound to have significant in vivo activity against Klebsiella pneumoniaein mice when administered orally at a dose level of 400 mg./kg./d.

EXAMPLE 29 1-Ethyl4-oxo-7-propionoxymethyll ,8-naphthyridine-3-carboxylic acid was prepared following the procedure described inExample 160 using 2 g. of l-ethyl-8-hydrox- 18ymethyl-4-oxo-l,8-naphthyridine-3-carboxylic acid, 6 cc. of propionicanhydride and about 50 cc. of pyridine. There was thus obtained [.54 g.of the product, 1-ethyl-4-oxo-7-propionoxymethyl-1,8-naphthyridine-3-carboxylic acid, m.p. l49.8-151.0C. (corr.), after one recrystallization from ethanol.

Anal. Calcd. for C l-1 N 0 C, 59.20; H, 5.30; N, 9.21.

Found: C, 58.86; H, 4.97; N, 9.46.

l-Ethyl-4-oxo-7-propionoxymethyll ,8-naphthyridine-3- carboxylic acidwas found to have significant in vivo activity against Klebsiellapneumoniae in rmce when administered orally at a dose level of 200mg./kg./d. I

EXAMPLE 30 7-Butyroxymethyl-l-ethyl-4-oxo-1 ,8-napthyridine-3-car- Aboxylic acid was prepared following the procedure described in Example27 using 2 g. of l-ethyl-7-hydroxymethyl-4oxo-1,8-naphthyridine-3-carboxylic acid, about 8 cc. of butyric anhydrideand about 50 cc. of pyridine. There was thus obtained 1.76 g. of theproduct, 7-butyroxymethyl-1-ethyl-4-oxol ,8- naphthyridine-3-carboxylicacid, m.p. l28. 2-129.4 C. (corr. after one recrystallization fromethanol-water.

Anal. Calcd. for C l-l N O z C, 60.37; H, 5.70; N, 8.80.-

Found: C, 59.88; H, 5.47; N, 9.10. 1

7-Butyroxymethyll -ethy1-4-oxo-l ,8-naphthyridine-3-carboxylic acid wasfound to have significant in vivo activity against Klebsiella pneumoniaein mice when administered orally at a dose level of b 200 mg./kg./d.

We claim:

1. A compound of the formula where Z is COOH or COO-alkyl, alkyl in eachinstance has from one to six carbon atoms, and acyl has from one to sixcarbon atoms and is selected from alkanoyl, monoor di-haloalkanoyl,carboxy-alkanoyl or dialkylaminoalkanoyl.

2. 7-Acetoxymethyll -ethyl-4-oxol ,8-naphthyridine-3 -carboxylic acidaccording to claim 1.

3. 7-(Diethylaminoacetoxymethyl)-l-ethyl-4-oxo-1,8-naphthyridine-3-carboxylic acid according to claim 1.

4. 7-Chloroacetoxymethyl- 1-ethy1-4-oxol ,8- naphthyridine-B-carboxylicacid according to claim 1.

5. 7-Acetoxymethyl-l-n-propyl-4-oxo-1 ,8-naphthyridine-3- carboxylicacid according to claim 1.

6. 7-Dichloroacetoxymethyl-1-ethyl-4-oxol ,8- naphthyridine-3-carboxylicacid according to claim 1.

7. 7-lsobutyroxymethyll -ethy1-4-oxol ,8-naphthyridine-3- carboxylicacid according to claim 1.

8. 1-Ethyl-4-oxo-7-succinoxymethyll ,8-naphthyridine-3- carboxylic acidaccording to claim 1.

9. 1-Ethy1-4-oxo-7-propionoxymethyl-1 ,8-naphthyridine-3- carboxylicacid according to claim 1.

l0. 7-Butyroxymethyl-1-ethyl-4-oxo-l ,8-naphthyn'dine-3- carboxylic acidaccording to claim 1.

2. 7-Acetoxymethyl-1-ethyl-4-oxo-1,8-naphthyridine-3-carboxylic acidaccording to claim
 1. 3.7-(Diethylaminoacetoxymethyl)-1-ethyl-4-oxo-1,8-naphthyridine-3-carboxylicacid according to claim
 1. 4.7-Chloroacetoxymethyl-1-ethyl-4-oxo-1,8-naphthyridine-3-carboxylic acidaccording to claim
 1. 5.7-Acetoxymethyl-1-n-propyl-4-oxo-1,8-naphthyridine-3-carboxylic acidaccording to claim
 1. 6.7-Dichloroacetoxymethyl-1-ethyl-4-oxo-1,8-naphthyridine-3-carboxylicacid according to claim
 1. 7.7-Isobutyroxymethyl-1-ethyl-4-oxo-1,8-naphthyridine-3-carboxylic acidaccording to claim
 1. 8.1-Ethyl-4-oxo-7-succinoxymethyl-1,8-naphthyridine-3-carboxylic acidaccording to claim
 1. 9.1-Ethyl-4-oxo-7-propionoxymethyl-1,8-naphthyridine-3-carboxylic acidaccording to claim
 1. 10.7-Butyroxymethyl-1-ethyl-4-oxo-1,8-naphthyridine-3-carboxylic acidaccording to claim 1.